Fluid delivery for localized delivery of molecules into tissues in a patient and transfection and/or introduction of materials into cells suffers from limitations of existing technologies. Delivering a fluid containing an agent to a localized spot within a patient is an important fluid delivery method for a variety of treatments, such as localized delivery of antibiotics, the treatment of diabetes, various genetic disorders, novel cancer treatments, and an expanding number of cosmetic uses. Specifically, transdermal delivery refers to delivering an agent by crossing a skin of the patient. As an example, transdermal delivery of antibiotics is preferably used in treating skin and soft tissue infections. This localized treatment can be especially important where traditional oral and/or intravenous delivery mechanisms are ineffective or less-than-ideal, or a combination of different delivery devices and methods can be used together to improve delivery results. It can also be important to deliver large molecules such as plasmids or vectors into cells over a localized surface, such as into skin cells.
Using a transdermal delivery approach for localized delivery is superior to hypodermic injections because hypodermic injections can be painful, risk infection via needle reuse or misuse, and can create medical waste.
There are several approaches to transdermal delivery, each of which range in terms of effectiveness for particular applications. Transdermal patches can be applied directly to the outer layer of the skin. However, the patches only penetrate through the stratum corneum, which is only about 10 μm thick. Thus the vast majority of molecules cannot cross the stratum corneum. There is also a risk of infection due to the requirement for direct contact with the skin.
Other approaches involve the use chemical enhancers and iontophoresis. Another approach is the use of ultrasound. Electroporation, or the use of voltage pulses, has also been used for transdermal delivery. Microneedles are also used in transdermal delivery, consisting of very short needles that physically pierce the stratum corneum and thereby allow small molecules to cross the barrier of a patient's skin. Microneedles increase skin permeability by creating micron-sized holes in the skin layer to create an opening for small molecules. However, all of these approaches can irritate the skin and many are too expensive to be of wide-spread use.
The current approaches to delivery of an agent are therefore inadequate and there remains a need for devices and methods for providing local delivery of an agent to tissue in a manner that can be easily administered, and/or that causes as little skin irritation and pain as possible.
Methods of fluid delivery for transfecting cells with a range of molecules including but not limited to DNA, RNA, plasmids, and proteins also suffer from current limitations. Delivery into cells is crucial for gene therapy and for use with CRISPR editing methods. Standard approaches for introducing materials into cells include: electroporation in which voltage is applied across the cell membrane to create pores that allow material to enter, use of chemical transfection reagents (such as Lipofectamine) that use liposomal delivery, microinjection, and use of cell penetrating peptides (CPP).
Most of these methods lead to significant cell death because of shock to the cell. In several cases, electroporation or chemical transfection is not compatible with several subsets of cells that are sensitive to their surrounding environments and are prone to cell death via standard methods of delivery. Efficient and non-toxic delivery is especially a challenge for cells that are not in high abundance (such as populations of T-cells that are isolated from a patient and transected with genes for CAR-T therapy). In these cases, methods with high toxicity will severely impact the efficacy of treatment with genetically altered cells.
Large molecules cannot be locally delivered into cells in patients using any of these methods. Often, viruses are used to transfect genes into patient cells, but this approach has limitations and can lead to several off-target effects.
There is a need for gentler, more effective, localized approaches to deliver a variety of types of molecules into cell lines for use in a variety of settings, for example as a research tool or in therapeutic settings. The present disclosure thus provides methods, systems, and devices for more effective delivery of fluid.